title: Population pharmacokinetics of tolvaptan in healthy subjects and patients with hyponatremia secondary to congestive heart failure or hepatic cirrhosis.
abstract: Tolvaptan is a selective V2 -receptor antagonist used to treat hypervolemic and euvolemic hyponatremia. A population pharmacokinetic (PK) analysis was performed for tolvaptan in NONMEM® based upon data obtained from three trials conducted in 93 healthy subjects and six trials conducted in 628 congestive heart failure (CHF) patients or 24 hepatic cirrhosis patients receiving oral tolvaptan (5 to 240 mg). A two-compartment model with first-order absorption and elimination best described tolvaptan PK. Relative oral bioavailability was modeled relative to 100% for a 30 mg dose and ranged from 79.4% to 122%. Body weight and the impact of CHF or hepatic cirrhosis relative to healthy subjects were statistically significant (p < 0.001) predictors of both the apparent oral clearance (CL/F) and apparent central volume of distribution (Vc /F). The CL/F was reduced to 58.2% for New York Heart Association (NYHA) Class 1 or 2 CHF, 45.5% for NYHA Class 3 or 4 CHF, and 58.0% for hepatic cirrhosis relative to healthy subjects. Vc /F was reduced to 59.9% for NYHA Class 1 or 2 CHF and 51.3% for NYHA Class 3 or 4 CHF, and was 64.8% larger for severe hepatic cirrhosis (Child-Pugh score ≥ 10) relative to healthy subjects. A slight additional decrease in CL/F of 18.3% was also detected for patients with moderate hyponatremia (serum sodium of 115-130 mEq/l) after adjusting for CHF or cirrhosis (p < 0.001). This population PK model enabled assessment of tolvaptan PK with varying degrees of CHF and hepatic cirrhosis with fluid overload and may be used to explore PK-PD relationships with respect to fluid and electrolyte balance.
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, NY 12110, USA. svanwart@icpd.com
authors.forename: Scott A
authors.initials: SA
authors.lastname: Van Wart
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.forename: Suresh
authors.initials: S
authors.lastname: Mallikaarjun
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000150:complications; D006801:Humans; D007010:Hyponatremia / Q000097:blood* / Q000209:etiology; D008103:Liver Cirrhosis / Q000097:blood* / Q000150:complications; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000077602:Tolvaptan; D055815:Young Adult
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan
keywords: cirrhosis; heart failure; hyponatremia; pharmacokinetics; tolvaptan